Alzheimer's disease is a degenerative disease of the human central nervous system, which is mainly characterized by chronic, progressive cognitive impairment and memory damage. It is manifested by senile plaques, neurofibrillary tangles and neuronal loss, which has a strong impact on the cognition, memory, linguistic function, and living abilities, emotion and personality of the patients. At present, “cholinergic depletion theory” is well-acceptable worldwide for the pathogenesis of Alzheimer's disease. It is believed by the theory that the depletion of neurotransmitter—acetylcholine is a key factor for Alzheimer's disease.
Cholinesterase is a critical enzyme in biological nerve conduction, and in the cholinergic synapses, it is capable of degrading acetylcholine, terminating the excitation effect of neurotransmitter on the postsynaptic membrane, and ensuring normal transmission of nerve signals within an organism. However, acetylcholinesterase may result in the depletion of acetylcholine due to its capability of catalyzing the cleavage reaction of acetylcholine, further leading to the failure of signal transmission and the influence on the organism's functions such as cognition, memory etc. At present, for the purpose of treating of Alzheimer's disease, the activity of cholinesterase is usually inhibited by an acetylcholinesterase inhibitor so as to slow down the hydrolysis rate of acetylcholine and enhance the acetylcholine level in the synaptic cleft.
Vascular dementia is an acquired syndrome of intelligent damage caused by various cerebrovascular diseases, with the clinical manifestations including intellectual deterioration in memory, calculation, attention and execution etc., and it is now the most common causes for dementia behind Alzheimer's disease. It is thought by researchers that one of the damage mechanisms is cerebral infarction, ischemic and hypoxic hypoperfusion and hemorrhage pathology, which result in the reduction of the brain tissue volume, delayed neuronal death, and further lead to the intracerebral acetylcholinergic nerve damage, the decrease in acetylcholine release, and gradual appearance of dysmnesia, cognitive impairment, and declined society and daily life function. Administration of acetylcholinesterase inhibitor will improve the cognition, execution and activities of daily life of the patients.
Another mechanism of damage to the cerebral cortical neurons in the patients of vascular dementia is the increased influx of calcium into the brain, which results in the decline in the study and memory function. If the calcium channel antagonists such as nimodipine enter into the brain tissue and reversibly bind with the calcium channel related receptor, so as to suppress the influx of calcium ion into neurocytes, advantages can be achieved, such as improved tolerance to ischemia, dilation of cerebral vessels and improvement of cerebral blood supply, protection of neurons, and efficient improvement of the cognition of the patients of vascular dementia.
However, there is no compound that not only can inhibit the activity of acetylcholinesterase, but also can block the influx of extracellular calcium ions into cells through the calcium channel at present, and thus, it is of great importance to develop such type of compounds.